PROGESTERONE REGULATION OF ENDOMETRIAL ESTROGEN-RECEPTOR AND CELL-PROLIFERATION DURING THE LATE PROLIFERATIVE AND SECRETORY PHASE IN ARTIFICIAL MENSTRUAL CYCLES IN THE RHESUS-MONKEY

Progesterone (P) down-regulation of uterine estradiol (E) receptor (ER) appears to be a general mechanism by which P modulates E action in the uterus. Our present studies focus on the regulation of ER by P during die changeover from E to P dominance during artificial menstrual cycles in the rhesus monkey. Because of differential cell-type response and the cellular zonation of the primate uterus, we used immunohistochemical analysis in addition to biochemical assays to study the regulation of ER by P. Ki-67 immunoreactivity was used as an index of endometrial proliferation. We performed our analyses on Days 13 (peak of E), 14 (declining E and rising P), 17 (basal E and rising P), and 21 (basal E and peak P). ER immunoreactivity was present throughout the endometrium in luminal and glandular epithelia and stromal fibroblasts on Day 13. As E was withdrawn and P rose on Day 14 there were few distinct changes in ER staining in stromal and epithelial cells. On Day 17, immunoreactive staining showed a distinct reduction for stromal cells in all zones. Although luminal epithelial cells showed a decrease in immunoreactivity on Day 17, zones II, III, and IV retained positive staining for ER in glandular epithelia. ER staining in stromal cells on Day 21 was similar to the pattern observed on Day 17, whereas epithelial cells in zones I, II, and III showed a reduction in staining. Glandular epithelia in zone IV maintained strong positive staining for ER on Day 21. According to biochemical assays, total and occupied nuclear ER and cytosolic ER were significantly decreased on Day 14 and remained suppressed through Day 21. Endometrial proliferation (Ki-67 immunoreactivity) occurred throughout the endometrium on Day 13, showed little change on Day 14, and was dramatically suppressed in stromal fibroblasts and epithelial cells of zones I, II, and III on Days 17 and 21. Proliferation continued in glandular epithelium of zone IV during the changeover from E to P dominance. Removal of secretory estradiol (all E implants removed on Day 13) did not affect the proliferation pattern in zone IV on Day 21. Therefore, proliferation of glandular epithelial cells in zone IV is not dependent on secretory E. These results describe the temporal changes in ER immunostaining during the onset of P action in artificial menstrual cycles and demonstrate that not only are there zone-dependent differences in response to P but also that the sensitivity of different cell-types within the endometrium is subject to temporal differences in response. The coincident temporal and zone-dependent decrease in proliferation and ER in zones I, II, and III suggests a close relationship between P-dependent down-regulation of ER and endometrial proliferation.